Substituted tetrahydrofuran molecules are becoming of greater importance in pharmaceutical and agrochemical applications. 3,4-Epoxytetrahydrofuran (EpTHF) is an important building block for many of these substituted tetrahydrofurans. For example, EpTHF has been used to prepare anti-HCMVP agents (Wang, et al. Can. Biorg. Med. Chem. Lett. 1997, 7, 2567) and antibacterial agents (Kirkup and Boland, Eur. Pat. Appl. EP 238285, 1987). The preparation of EpTHF has been reported through standard oxidation techniques using peracids, but these reactions are rather slow and product isolation is difficult. In addition, there are safety concerns about contacting a peracid species with a known peroxide former such as 2,5-dihydrofuran.
An alternative method for the preparation of epoxides involves the initial formation of a halohydrin of the olefin followed by ring-closure under basic conditions. This method avoids the use of a strong oxidant but does require an efficient halohydrin formation. The halohydrin of the olefin is normally formed by the reaction of the corresponding hypohalous acid (normally formed in situ) with the olefin.
Sources of the hypohalous acid include a mixture of the halogen (bromine or chlorine) with water, acidification of the hypohalite anion (especially sodium or calcium hypochlorite), or N-haloacetamide or N-halosuccinimide in water. Indeed, 3-bromo-4-hydroxytetrahydrofuran has been prepared by the action of aqueous N-bromosuccinimide on 2,5-dihydrofuran (Kirkup and Boland, Eur. Pat. Appl. EP 238285, 1987; Baker and Wiemer, J. Org. Chem. 1998, 63, 2613). However, the selectivity of these halide sources when forming halohydrins is poor because of competing reactions.
Halohydrin forming reactions all suffer from the presence of two divergent pathways: the formation of halohydrin and the formation of dihalide. For example, as illustrated by the reaction scheme A outlined below, upon reaction with 2,5-dihydrofuran (2,5-DHF), two reaction products are formed. ##STR2##
In reaction scheme A, the desired halohydrin 1 and the undesired dihalide 2 are formed from the 2,5-dihydrofuran. This is particularly the case when using bromine in water, in which the dibromide 2b is the major product. The use of freshly recrystallized N-bromosuccinimide as the bromine source does not afford clean conversion to 1b, because even in this case 14% of the undesired dibromide 2b is formed. Moreover, the use of dilute sodium hypochlorite (acidified with hydrochloric acid) affords significant amounts (15-25%) of the dichloride 2a.
The brominating agent 1,3-dibromo-5,5-dimethylhydantoin has also been used for bromohydrin preparation (Coe et al., J. Chem. Soc. Perkin I, 1991, 2373). However, 1,3-dibromo-5,5-dimethylhydantoin has not been used to form bromohydrins of water-miscible olefins. Moreover, 1,3-dibromo-5,5-dimethylhydantoin has previously been used mainly as an oxidant, for allylic bromination of olefins, or for aromatic brominations. The allylic bromination and aromatic bromination reactions are substitution reactions that often proceed via a free radical mechanism. In contrast, in accordance with the discoveries of the present invention, bromohydrin formation from an olefin using 1,3-dibromo-5,5-dimethylhydantoin is an electrophilic addition reaction that adds two species to the olefin and generally proceeds via an ionic mechanism. There is no precedent that suggests superior selectivity for bromohydrin formation when using 1,3-dibromo-5,5-dimethylhydantoin as compared to other electrophilic bromine sources.
Therefore, a process that improves the selective conversion of a water-miscible olefin to halohydrin is still needed. The present invention solves this problem by providing such an improved process.